Human Papilloma Virus (HPV) related oropharynx cancer (HPVOPC) is increasing in the US and now exceeds the incidence of cervical cancer. Patients with recurrent HPVOPC have an improved survival when compared to HPV negative OPC patients, and a majority of these patients have an opportunity for durable disease control. In general, these data imply that effective early detection of recurrent disease in HPVOPC patients offers an opportunity to effectively salvage patients with recurrent/metastatic disease. Recent studies have indicated that HPV16 DNA in plasma or salivary rinses may be used as a marker for disease in HPVOPC, and that there may adequate lead time between detection and recurrence to clinically intervene in patients with HPV16 DNA in saliva and/or plasma. Accordingly, we have developed a novel, genomic based saliva/plasma test for HPV16 DNA in a CLIA certified clinical laboratory. The overall hypothesis of this proposal is that validation of a HPV16 DNA assay in plasma/salivary rinse as a biomarker for high risk HPVOPC in a prospective trial will provide independent prognostic data, facilitate treatment stratification for patients at high risk of recurrence, and provide lead-time to detection of recurrence that will allow for earlier detection and treatment. This will identify a high-risk cohort of patients with HPVOPC for whom prognosis can be improved with intensified surveillance and treatment. We anticipate that rigorous evaluation of the potential of HPV16 DNA in plasma and saliva in HPVOPC patients will establish the value of this biomarker in identification of patients at high risk for recurrence and can be rapidly translated to clinical usage.